Elevated phospho-S6 expression is associated with metastasis in adenocarcinoma of the lung.
Elevated phospho-S6 expression is associated with metastasis in adenocarcinoma of the lung.
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DOI：
10.1158/1078-0432.ccr-08-0565
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Aldape K
中科院分区：
文献类型：
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作者：
McDonald JM;Pelloski CE;Ledoux A;Sun M;Raso G;Komaki R;Wistuba II;Bekele BN;Aldape K
本研究的主要目的是确定Akt通路的分化和激活标志物是否与肺腺癌的转移相关。配对的原发性和转移性肿瘤样本来自41名接受原发性肺腺癌和脑转移病灶切除术的患者。比较成对样本的TTF-1和E-钙粘蛋白的相对表达，作为潜在的分化标志物。通过p-Akt和p-S6的表达评估Akt途径的激活。然后在77个原发性肺腺癌的队列中评估在匹配对之间表现出相对不一致的表达的生物标志物。在82例原发性肺腺癌的独立队列中进行验证。在41对配对中，E-cadherin（23对不一致）和TTF-1（18对不一致）在原发性肿瘤中过表达（分别为20/23和15/18）。相反，p-S6过表达与转移性肿瘤显著相关（21对不一致对中的20对）。77例原发性肺腺癌中检测了E-cadherin、p-S6和TTF-1的表达，其中p-S6高表达与较短的转移时间相关。然后在一组独立的82个肿瘤中验证p-S6与转移的关联。在多变量分析中，p-S6表达是调整肿瘤分期后无转移生存率的负向独立预测因子。p-S6在转移性肿瘤中过表达。在原发性肿瘤中，较高的p-S6表达与较短的无转移生存期相关。该生物标志物在未来的临床试验中具有风险分层的潜力。
The primary objective of this study was to determine whether markers of differentiation and activation of the Akt pathway are associated with metastasis in adenocarcinoma of the lung. Paired primary and metastatic tumor samples were obtained from 41 patients who had undergone resection of both primary lung adenocarcinoma and brain metastatic lesions. Paired samples were compared for relative expression of TTF-1 and E-cadherin as potential markers of differentiation. Activation of the Akt pathway was assessed by expression of p-Akt and p-S6. Biomarkers which showed relative discordance in expression between the matched pairs were then assessed in a cohort of 77 primary lung adenocarcinomas. Validation was performed in an independent cohort of 82 primary lung adenocarcinomas. Among the 41 matched pairs, E-cadherin (23 discordant pairs) and TTF-1 (18 discordant pairs) were overexpressed in primary tumors (20/23 and 15/18, respectively). In contrast, p-S6 overexpression was significantly associated with metastatic tumors (20 of 21 discordant pairs). The expression of E-cadherin, p-S6 and TTF-1 was evaluated in 77 primary lung adenocarcinomas, where high p-S6 expression was associated with shorter time to metastasis. The association of p-S6 with metastasis was then validated in an independent set of 82 tumors. In multivariable analysis, p-S6 expression was a negative independent predictor of metastasis-free survival after adjustment for tumor stage. p-S6 is overexpressed in metastatic tumors. In primary tumors, higher p-S6 expression is associated with shorter metastatic-free survival. This biomarker has the potential for risk stratification in future clinical trials.